The intrauterine renin–angiotensin system: Sex‐specific effects on the prevalence of spontaneous preterm birth

Abstract

Preterm birth (PTB) is the single largest cause of death in infants and young children. The rate of PTB is significantly higher in male infants, particularly those that are born very preterm. Here we present evidence to suggest that the decidual renin-angiotensin system may play a role in inhibiting inflammation and maintaining the integrity of the fetal membranes during pregnancy, and that sex-specific alterations in the intrauterine RAS could contribute to the increased risk of PTB in male babies. Women carrying female fetuses have high levels of expression of decidual prorenin at term. Decidua from 'female' pregnancies also have greater expression of the anti-inflammatory angiotensin (Ang)-(1-7) pathway, than decidua from 'male' pregnancies, and have lower levels of the pro-inflammatory Ang II pathway. We propose that in 'female' pregnancies, the very high levels of decidual prorenin drive the anti-inflammatory Ang-(1-7) pathway, thus reducing the likelihood of PTB. In addition, the high levels of prorenin produced by the decidua in 'female' pregnancies are able to diffuse into the amnion and bind to the PRR. We postulate that PRR/prorenin interactions, possibly through both angiotensin dependent and independent pathways, stimulate the production of ECM proteins, inhibit ECM degradation and prevent apoptosis, thus strengthening the amnion. Thus control of the inflammatory signature and the integrity of the fetal membranes prior to parturition may partly depend on the sexually determined activity of the decidual and amniotic renin-angiotensin system pathways.

Tryptophan degradation enzymes and Angiotensin (1−7) expression in human placenta

“…The detection of a co-expression of Ang(1− 7) and TDO in healthy placentas, which we found to be more represented in the villi and fetal side of the placenta compared to the maternal side, is a novel finding, and suggests the existence of an interaction between the KP and RAS in pregnancy. All components of the intrauterine RAS have been identified in term human decidua, myometrium, and fetal membranes (Pringle et al, 2017(Pringle et al, , 2011 and they are involved in placental development through processes such as angiogenesis, modulation of placental blood flow.…”

Genetic Association of Angiotensin-Converting Enzyme (ACE) Gene I/D Polymorphism with Preterm Birth in Korean Women: Case-Control Study and Meta-Analysis

“…Angiotensin II stimulates the secretion of aldosterone, which regulates uteroplacental vasoconstriction and blood pressure [9]. Previous studies have shown that an increase in uteroplacental blood pressure is associated with the development of PTB, preeclampsia, and spontaneous abortion [10,11,12].…”